The long term objective of this proposal is to gain insight into mechanisms of innate immunity to infectious agents in humans. Our discovery that TLR2 mediates the innate immune response to microbial lipoproteins, prompted us to investigate the regulation of innate immune response, finding that the selective induction of IL- 10 and IL 15, differentially programs macrophages for phagocytosis vs. antimicrobial responses in leprosy. The differential regulation of these pathways optimizes antimicrobial efficiency required for host defense against microbial pathogens, yet the divergence of these programs can also contribute to the pathogenesis of infectious disease. By investigating leprosy as a model, and its causative pathogen, Mycobacterium leprae (mLEP), we hope to gain insight into the innate immune mechanisms that instruct the macrophage functional programs that contribute to pathogenesis and host resistance. We therefore propose to: 1) determine the mechanisms by which mLEP, through distinct ligands, triggers innate immune receptors to differentially induce macrophage phagocytic and antimicrobial programs, 2) elucidate the mechanisms by which the local cytokine environment contributes to divergence of the macrophage functional programs in leprosy; and 3) investigate the mechanisms by which specific miRNAs regulate the phagocytic vs. antimicrobial innate immune responses in leprosy. Together these aims target an integrated understanding by which the innate immune response is programmed with relevance to host defense against microbial infection in humans, starting with the trigger (Aim 1), mechanisms of cytokine amplification (Aim 2) and molecular regulation (Aim 3) leading to the final functional programs at the site of infection in leprosy.